AB0433 ANTI-RITUXIMAB ANTIBODIES DEMONSTRATE NEUTRALISING CAPACITY, ASSOCIATE WITH LOWER CIRCULATING DRUG LEVELS AND EARLY RELAPSE IN PATIENTS UNDERGOING TREATMENT FOR SYSTEMIC LUPUS ERYTHEMATOSUS
Authors: C. Wincup, N. Dunn, C. Ruetsch-Chelli, A. Manouchehrinia, N. Kharlamova, M. Naja, B. Seitz-Polski, D. Isenberg, A. Fogdell-Hahn, C. Ciurtin, E. Jury
Journal: Annals of the Rheumatic Diseases (2022)

Background A major limitation of biologic therapy is formation of anti-drug antibodies (ADA). We previously found ADA to rituximab (RTX) are more prevalent in patients undergoing treatment for systemic lupus erythematosus (SLE) than rheumatoid arthritis and vasculitis (1). In addition, we demonstrated that ADA to RTX predict subsequent infusion related reactions (2). However, little is known regarding the long-term dynamics of ADA to RTX in patients undergoing treatment for SLE. Objectives In this study we evaluated the longitudinal impact of ADA positivity with particular focus on; 1) Risk factors for development of ADA. 2) Impact of ADA on treatment response. 3) Influence of ADA on RTX drug kinetics over time. 4) The capacity of ADA to neutralise RTX. Methods Patients with SLE undergoing treatment with RTX were recruited to this study (n=35). Serum samples were collected at the following intervals post-treatment; 1-3 months (defined as ‘early’ post-treatment), 6 months, 12 months, 36 months (n=114). Clinical and laboratory data was collected pre-treatment and at each follow-up time point. Response to treatment was assessed by improvement in SLEDAI-2K score from baseline and also according to BILAG as previously described (3). ADA were detected using an electrochemiluminescent immunoassay. Serum RTX levels were measured by ELISA. ADA status was defined according to the following patterns over time; persistently negative, persistently positive (0-15 AU/ml) and persistently high positive (≥16 AU/ml, upper quartile). A complement dependent cytotoxic assay was used to determine neutralising capability of ADA in a subgroup of positive samples (n=38). Results ADA to RTX were found to be persistently positive in 64.3% of patients over the 36-month follow-up period and there was no significant difference in baseline disease activity (BILAG / SLEDAI-2K) between those who were subsequently ADA positive vs negative. ADA positive patients had a younger age at diagnosis of SLE when compared with ADA negative (mean 22.50 ± 9.10 vs 37.29 ± 11.31 years, p=0.002, Figure 1 A). Multivariate logistic regression found a 22% decrease in risk of ADA positivity for each addition year after diagnosis (p=0.03). Figure 1. ADA positive patients had a significantly lower C3 level at baseline (mean 0.61 ± 0.23 g/L vs 0.87 ± 0.30 g/L, p=0.026), which remained lower at each subsequent time point post-treatment up to 12 months post-treatment (Figure 1B). At 1-3 months post-RTX, patients who were ADA positive had a significantly lower circulating drug level than ADA negative (p&lt;0.001, Figure 1 C). In terms of clinical response, ADA positive patients had an initial significant improvement in disease activity (SLEDAI-2K) by 3 months (p&lt;0.001). However, response was not maintained at 12 months (Figure 1 D). In comparison, ADA negative patients showed a significant improvement in SLEDAI-2K at 6 months and this was maintained across the 36-month follow-up period (Figure 1 E). BILAG defined relapse was more common at six months post-treatment in ADA positive patients (22%) and ADA highly positive patients (33%) than those who were ADA negative (in which there were no cases of relapse within the first six months, Figure 1 F). At 12-months post-RTX, a higher rate of BILAG defined Major Response was seen in those who were ADA negative (80%) when compared with ADA positive (44%) and high positive (36%) as shown in Figure 1 G. Finally, antibodies derived from all ADA positive samples (38/38) were found to neutralise RTX in vitro . Conclusion ADA to RTX were common and persisted over the 36-month period of this study. ADA associated with earlier serum drug elimination, increased relapse rates and demonstrated neutralising capacity suggesting that ADA could be a significant limitation to sustained response to treatment in clinical practice. References [1]Faustini F et al. Arthritis research &amp; therapy. 2021;23(1):211 [2]Wincup C et al. Annals of the rheumatic diseases. 2019;78(8):1140-2 [3]Md Yusof MY et al Annals of the rheumatic diseases. 2017;76(11):1829-36 Disclosure of Interests None declared